Monday, August 20, 2012

A Possible Cure for HIV

A Possible Cure for HIV 

 

Patients who have recently been able to clear or control their acquired immune deficiency syndrome (AIDS) have renewed the interest of scientists in finding a cure for the human immunodeficiency virus (HIV) and subsequently, AIDS. The newest ideas to help generate a cure include transplants of naturally resistant stem cells or the genetic modification of immune cells to render them immune to the virus (Pollack 2011). Since people with HIV are required to take antiviral drugs to control the infection for the rest of their lives the discovery of a cure would improve countless lives and solve one of the world’s foremost health issues.

HIV is a retrovirus which attacks the cells of the human immune system, causing their inability to function. As the HIV infection advances, the immune system of the person gradually weakens, making them more vulnerable to other illnesses. The last stage of the HIV infection, AIDS, usually takes 10-15 years to reach and antiviral drugs can slow the development down even further (World Health Organisation 2012).
In the first patient, a man seemingly cleared his HIV infection through numerous bone-marrow transplants he received as leukemia treatment. The donor was one of the 1% of Northern Europeans that lack a protein, CCR5, rendering him naturally resistant to HIV. Due to the bone-marrow (stem cell) implant the patient is able to produce a resistant immune system and has been free of the virus for four years (CBS News 2011). However, this approach for a cure is unlikely due to the difficulties of finding a matching donor as well as the transplant procedure being risky and expensive. In addition, donors would be unethically ‘farmed’ for bone-marrow. Therefore this approach for a cure is highly improbable.

Scientists attempted to modify the immune cells of the second patient, eliminating the CCR5 protein, in order to make them resistant to HIV. White blood cells were removed from the body of the patient and put through gene therapy which modified the cells to produce another protein which disrupted the CCR5 protein. The treated cells were replaced into the man’s body and a month later the man stopped taking antiviral drugs as part of the experiment. Initially, the amount of HIV rose sharply, as expected, but then dropped to an undetectable level gradually while immune cell counts rose. However, the gene therapy did not work as well in 5 other patients (Pollack 2011). This approach to a cure is unproven through these patients but is still being developed, moving onto further clinical trials earlier this year (Instinct Staff 2012). This idea presents numerous problems, the main one being that each individual would have to undergo the procedure making this cure implausible at this point.

Although there is great need of a cure for HIV, with the current methods and ideas involving stem cell transplants and gene modifications, it is doubtful that a functional cure that can be used on a wide scale will be found in the near future.

Gene Therapy Restores Vision

Gene therapy is an exciting treatment option that is starting to take off in the field of treating genetic diseases. Three women in the United States, who had previously been treated for genetic blindness with gene therapy in one eye, have been treated in the second eye, and the results are looking promising (http://www.bbc.co.uk/news/health-16942795). Gene therapy is still only in its early stages as a treatment option, but the promise of recent studies into its success in treating genetic eye diseases mean this technology is on the rise and could soon become a widespread treatment option throughout the world.

Genetic disorders are caused by the malfunctioning of one or more of our genes, which prevent the proteins in our body, which are instructed by the genes, from fulfilling their normal functions (http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml). In gene therapy, the malfunctioning gene is replaced by a new, better-functioning gene, which is inserted into the area of the body where the faulty gene is located (http://www.scientificamerican.com/article.cfm?id=experts-gene-therapy). If we do not replace this malfunctioning gene, it can be the cause of disease within in the body. Gene therapy was first tested for treating genetic blindness back in 2008, when a research team at Moorfields Eye Hospital’s NIHR Biomedical Research Centre in the UK used gene therapy successfully on the eyes of human patients, proving it was safe and helped to improve their sight (http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml).

In early 2012, three women in the US were treated with a second round of gene therapy to relieve their genetic blindness, caused by an inherited condition known as Leber’s Congenital Amaurosis (LCA). LCA is a very rare disease, appearing just after birth, and occurring as cells from the retina, the “light-sensitive layer of cells at the back of the eye” (Briggs 2012), progressively die out over time, degrading the vision of the sufferer. It is caused by a faulty gene in the cells of the retina, RPE65, and gene therapy aims to fix this by injecting a virus containing a functioning version of the gene into the eye. Dr Jean Bennett, of the University of Pennsylvania’s Mahoney Institute of Neurological Sciences, first treated the three women with this method back in 2008. At the time, twelve people suffering from LCA were injected in just one eye, recovering some vision in the injected eye, and in early 2012, the three women were chosen out of the twelve to have the procedure repeated in the second eye, showing a notable improvement in the vision quality in both eyes. Information regarding Dr Bennett’s most recent results in this area can be found in the February 8th edition of Science Translational Medicine (http://stm.sciencemag.org/content/4/120/120ra15.full.html 2012).

It is evident that, in the last few years, gene therapy has started to emerge as a potentially successful treatment for genetic diseases, in particular those involving genetic blindness. Recent studies, such as the ones referred to above, have demonstrated gene therapy to be successful in improving vision quality for those suffering from inherited eye diseases, such as LCA, and have provided evidence that it is a safe treatment option. It is hoped that these discoveries will lead to more widespread use of gene therapy as a valid treatment for genetic blindness, and will improve the quality of life of those suffering from poor vision quality as a result of inherited eye conditions.

Wednesday, August 15, 2012

Genetics and Bacterial Resistance


Genetics and Bacterial Resistance

Bacteria have many mechanisms for adapting to their environment and they certainly use them when responding to adverse conditions. In particular, bacteria such as Eschericha coli go through many genetic mutations when building resistance to various antibiotics (Toprak et al. 2012). A team of scientists at Harvard have developed a method for recording and understanding these mutations in an experiment which could have future implications on the way we approach bacterial infections (stealth tactics of bacteria revealed, 2012).

aims to not only record, but understand precisely how bacteria forms a resistance to antibiotics. In order to control the present antibiotic, the concentration of that drug and to record how the bacterium responds, they created the ‘morbidostat’ (stealth tactics of bacteria revealed, 2012). Results have been obtained from E. coli as it was monitored about how it responded to controlled doses of various antibiotics.



The results showed that the bacteria developed resistance to all three of the introduced antibiotics (stealth tactics of bacteria revealed, 2012). Some antibiotics can be faulted by a single gene change, although in this case, like many others, a number of genetic mutations had to occur to obtain the desired phenotype (Toprak et al. 2012). The group of genetic mutations that occurred in this case targeted the bacteria’s susceptibility to each of the antibiotics. The way in which the bacteria responded to the three test drugs separately was a testament to the variability bacteria is capable of. Achaean organisms are widely recognized for their adaptive abilities, which stem from their methods of reproduction. High generational rates are achieved by the ability of the organisms to use binary fission.  Also, plasmids play a role in increasing the genetic material available to the bacteria (Campbell et al. 2009). These mechanisms give reason for the successful rapid mutation of genes measured within the experiment.

The mutations occurring within the bacteria differed between the types of antibiotic it was exposed to (Toprak et al. 2012). The differences between these changes can be applied to the way the bacteria’s resistance developed. But perhaps the most useful data that resulted from this experiment was the congruency between separated test populations.  The genomes of bacteria responding to the same drug, which were measured throughout the test, concluded that “parallel populations evolved similar mutations and acquired them in a similar order.” (Toprak et al. 2012, p101). The patterns that were observed suggests that there are specific pathways of mutation, along which bacteria moved to achieve a goal; antibiotic resistance (Toprak et al. 2012). Now that these genetic pathways have been measured, a more complex set of knowledge can be applied to improving antibiotics and increasing their effectiveness in the future.

A greater understanding of bacteria and it’s mechanisms for coping with its environment is being achieved through many studies being conducted, genetic resistance is a particularly relevant topic and developing improved ways of treating bacterial infections in humans is highly beneficial. The measurement of the response of bacteria to antibiotics has resulted in evidence of mutational pathways for bacteria gaining resistance (Toprak et al. 2012). These results are of great significance to the notions of improving the antibiotic method and overcoming bacterial resistance.

Finding the source of Individuality

Finding the source of Individuality

Have you ever wondered at the uniqueness of every individual around you? Including yourself. Even identical twins that have the same set of genes and have grown up together differ in some of their characteristics and personality. This brings up the old question of nature/ nurture. Recent research findings show that the answer may lie in certain type of DNA within a class called Mobile Genetic Elements (MGE). More specifically, the ones found moving in the brain are called Retratransposons.

Retratransposons like the Long Interspersed Element (L1) for example, follow a copy and paste method to move itself around. It is able to do this because it is thought that L1 retratransposons encode for all the ‘machinery’ it requires to move itself.  The original L1 segment of DNA first transcribes itself into its RNA form following which, the RNA strand moves out of the nucleus to synthesize the proteins in its code. This RNA strand and protein complex then re-enter the nucleus where one of the proteins, endonuclease creates nicks in the existing DNA. At this point, the RNA is retranscribed by the endonuclease into a double stranded DNA which is then inserted into the nicked area.



Transposon events cause the mosaicism
 seen in the color of corn kernels.

This was seen as fascinating because such an explicit change of the DNA within humans is not seen in any other cell excepting immune cells where it is necessary to help churn out new antibodies to fight new diseases.  Although mobile elements were discovered in the 1940’s by Barbara McClintock which resulted in the famous ‘multi-coloured’ corn, its presence and activity in human cells has been a recent discovery. Working with mice and post-mortem samples of the human brain, Professor Fred H. Gage and colleagues discovered that these mobile elements are ‘switched off’ in most human somatic cells except in the hippocampus in the brain from where new neurons are ‘born’. It was found that these mobile elements are extraordinarily active within the neural progenitor cells in the hippocampus with an average of 80-100 L1 jumps per cell. This find is particularly interesting due to the consequences of each jump.

neuron
During the early stages of human nervous system development LINE-1 elements become active (indicated by green flourescence) possibly affecting neuronal function.

When a L1 DNA segment inserts itself into a new area in the genome, it can have several different effects depending on insertion site. On occasion, the new DNA may not have any effect whatsoever. However, the other effects can either be good or bad. If the L1 insertion site is within a DNA segment coding for a protein, the insertion may disrupt the code thus preventing any protein being made or may produce a new variant of the protein. On the other hand, the L1 DNA can act as a promoter if it inserts itself just outside a coding segment in the DNA. This means that it can either ‘turn off’ or ‘turn on’ that segment resulting in the inhibition or production of a certain protein. On a wide scale, this leads to a huge amount of diversity between cells in the brain. As Gage says, “This is a potential mechanism to create the neural diversity that makes each person unique." Thus, this also makes humans “true chimeras”.


Retratransposons have garnered increased interest due to research showing that L1 insertions play a part in neurological and psychiatric conditions. Although further research is required to be carried out, this is a field that holds many promises and discoveries especially since up to 50% of the human DNA is made up of Mobile Elements.

Inheritance of Male Pattern Baldness

Inheritance of Male Pattern Baldness

The Genetics of Baldness - Stephen Connor (s4291526)
What is Male Pattern Baldness (MPB)?
Male pattern baldness (MPB) is a condition which most men (and some women) will face during their lives. MPB causes in people a receding hair line and their hair will become a lot thinner. In the later stages of MPB complete baldness around the crown and possibly the middle section of the top of the head can occur. But what causes male pattern baldness?





What causes MPB?

Testosterone is a steroid hormone that affects many different areas of the body and their functions, however it is not often realized that testosterone is also the cause of hair loss. When testosterone is in the presence of an enzyme called 5-alpha-reductase, the enzyme will break down testosterone into dihydrotestosterone, which is often referred to as DHT.

Male pattern baldness occurs as a result of hair follicles being sensitive to DHT. If a hair follicle is sensitive to DHT it will miniaturize and eventually no hair will grow where that hair follicle grew. It can be seen that through the process of miniaturizing and loss of hair how the symptoms of MPB are so (Receding hair line, thinning of hair). (WebMD 2010)

How does a person’s genetics affect their chance of having MPB?
In 2005, German researches discovered a gene on the X-chromosome that affects baldness (Dr Barry Starr 2006). This gene (androgen-receptor gene, AR) instructs the making of androgen-receptors (also known as dihydrotestosterone receptors).   If the AR gene allows too many androgen-receptors to be made in the scalp or in hair follicles it can result in more testosterone being on the scalp. This in turn results in the creation of more dihydrotestosterone which then leads to greater loss of hair.
Some people who have MPB have an AR gene that performs normally. This means the AR gene is not the only factor that influences the development of MPB. Two independent studies were conducted to discover a common factor that people with MPB had that people without MPB did not have. Both studies came to the conclusion that people suffering with MPB have changes on their chromosome 20 compared to those without MPB.
Everyone has two chromosome 20s, one from each parent. This allows for one chromosome 20 to be unchanged even though the other is changed. This shows that there are three different combinations of chromosome 20s a person can have (and therefore three different likelihoods of having MPB):

1.       Two unchanged chromosome 20s (0 times more likely to develop MPB)
2.       One unchanged and one changed chromosome 20 (3.7 times more likely to develop MPB)
3.       Two changed chromosome 20s (6.1 times more likely to develop MPB)
(Melinda Beck 2008)

Not just one factor affects the likeliness of developing male pattern baldness.  An AR gene that allows for too many androgen-receptors to be in the scalp or hair follicles will increase the chances of developing MPB dramatically. Certain variations to the chromosome 20 also increase the probability of having MPB. Variations on one chromosome 20 will increase the chance of having MPB by 3.7 times and having variations on both chromosome 20s will increase the chance by 6.1 times.

Designer Babies Preimplantation Genetic Diagnosis

Designer Babies – Preimplantation Genetic Diagnosis

Inheriting genes of unfavourable nature has plagued humanity since the dawn of time. And it was long before Gregor Mendel’s discovery of how our physical and behavioural traits are inherited, that humans had already established a desire for the customization of our off springs characterized by disease-free-inheritance matched by superior physical and behavioural genes such as good looks, intelligence and athleticism.  It was not until the beginning of the 21st century that scientists started making advances in this sensitive area of eugenics, colloquially termed designer baby – “a baby whose genetic make-up has been modified in order to eradicate a particular defect, or to ensure that a particular gene is present.”   In spite of the ethical concerns, scientists continue to put preimplantation genetic diagnosis (PGD) into practice, involving in vitro fertilization (IVF) to examine chromosomal abnormalities and perform procedures on the embryo’s DNA before implantation.
The biological causes of genetic variation is at the heart of what PGD aims to eliminate. The three most common mechanisms that arise from sexual reproduction are independent assortment of chromosomes, crossing over and random fertilization. Mendel’s Law of Independent Assortment tells us that during meiosis each pair of alleles segregates independently of each other pair of alleles. And thus, each sperm cell carries chromosomes with a unique combination of the male’s genes and it is by chance that any one of the sperm cells will fertilize the female’s egg – the random nature of fertilization. Finally, the crossing over of alleles results in recombinant chromosomes the uniquely combined DNA from both parents. A fourth less common mechanism, Mutations can also develop whereby DNA replication encompasses an error either during meiosis or mitosis in a zygote.   How can PGD reverse this variance at a cellular level?


PGD was originally developed to eradicate life-threatening diseases in unborn babies and to instill a sense of security in the mother, yet in more recent times it has gone one step further to enhance superficial features. PGD, first of all involves the fusion of gametes in the lab. Mitotic divisions form a cluster of embryo cells.  An incision is made through the membrane using acid and cells are removed. Each cell undergoes genetic analysis biopsy using Fluorescent in-situ Hybridization (FISH). Chemicals are used to illuminate chromosomes to correspond to a particular colour. A DNA probe is used to visualize the cell for genetic analysis. This process is repeated until a cell of favourable genes is found, which is implanted into the mother’s womb. All other cells are discarded, which brings up ethical concerns.





Figure 3: Unnatural Selection using PGD                                                            

Perhaps the practicality of PGD can be improved by maximizing its benefits while minimizing harm. Chromosomal analysis is quite often essential in couples, who carry balanced translocations, in advanced age women and women with previous children who have abnormal chromosome numbers. In addition, women experiencing recurrent pregnancy loss, recurring poor quality embryos or repeated IVF failures could also benefit from the PGD procedure to select healthy embryos. PGD can be arguably unethical due to its superficial and selective nature but its benefits looms large for those in need.